Approximately 160,000 men were diagnosed with prostate cancer (PCa) and around 30,000 died of PCa in 2017. Over 3.3 million men are surviving with PCa in the United States and this number is expected to increase to 4.5 million by 2026. Current therapeutic strategies for advanced castration-resistant prostate cancer (CRPC) include androgen receptor (AR) antagonists and a CYP17A1 inhibitor that prevents synthesis of androgens. Although these drugs extend the progression-free survival, approximately 30% of the tumors do not respond to these therapies and the remaining develops resistance shortly after treatment initiation. One of the primary reasons for CRPC relapse, despite these treatments, is expression of constitutively-active AR splice variants (AR-SV) that lack the ligand binding domain (LBD). To overcome this critical barrier, we discovered novel AR antagonists (Selective Androgen Receptor Degraders (SARDs)) that bind to the AR-activation function-1 domain (AF-1) in the N terminal domain (NTD) and/or LBD and antagonize and degrade AR and AR-SVs. The SARDs have unique pharmacologic properties that strongly and selectively antagonize the AR and degrade full length and splice variant AR (independent of LBD) in multiple models. These SARDs inhibit growth of prostate cancer cells and tumors that are dependent on AR full length and splice variants for growth. The SARDs we have tested thus far have poor bioavailability and drug-like properties. In order to overcome the poor bioavailability and to understand the mechanisms of action, we propose a) to develop novel SARDs that will inhibit and degrade full length and splice variants of the AR and will be orally bioavailable and b) to identify mechanisms by which the AR and its splice variants are degraded, resulting in drugs with better efficacy. Under aim-1 we will synthesize AR antagonists belonging to new generation of SARDs that will degrade the AR, inhibit prostate cancer growth, and will be orally bioavailable. We will synthesize and identify orally bioavailable SARDs and evaluate those using in vitro and in vivo PCa and CRPC models. These studies will result in highly potent new SARDs that will have drug-like properties. Under aim-2, we will identify the role of ubiquitination in AR and AR-SV degradation by discerning ubiquitin sites and characterizing their role in AR, AR-SV, and SARD action. Efforts will be dedicated in aim-3 to determine the scavenging role of SARDs and the implications of GATA-2 down-regulation for SARD function. The expected outcome of these studies will be new next generation drugs to treat aggressive CRPC, research tools to study AR degradation, better understanding of the AR and CRPC basic biology, and surrogate endpoints to advance these molecules to clinic.